Cisplatin (cis-diamminedichloroplatinum, cis-Pt(NH.sub.3).sub.2 Cl.sub.2, molecular weight 300.05) has been used as a chemotherapeutic agent for many years since the discovery of its anti-tumor activity by B. Rosenberg et al. (Nature, 1965, 205, 698;Nature, 1972, 222, 385).
After so many years, cisplatin is still being widely used because of its efficacy. It has been used to treat cancer patients for head, neck, ovarian cancer, etc. However, its major drawback, the toxicity, is still a big concern.
Many attempts have been made to modify the cisplatin molecule in order to reduce its toxicity; many other attempts have been made to understand the interaction between cisplatin and DNA, which is the ultimate target of cisplatin. A few attempts have also been made to modify the composition of cisplatin dosage form to reduce its toxicity or improve its efficacy.
In terms of modifying the cisplatin molecule, many people have attempted to change the ligand or ligands on Platinum. Examples of the modifications on cisplatin have been made by K. C. Tsou, et al.(J Clin. Hemat. Oncol. 1977, 7, 322,), R. J. Speeder et al. (J. Clin. Hemat. Oncol. 1977, 7, 210), A. Mathew et al. (Chem. Comm. 1979, 222), D. Rose, et al. (Cancer Treatment Reviews, 1985, 12, 1), and D. Alberts et al. (Cancer Treatment Reviews, 1985, 12, 83).
In terms of understanding the interaction between cisplatin and DNA, the X-ray structure of the adduct of cisplatin and DNA was determined by S. E. Sherman et al. (Science 1985, 230, 412). This critical work provides a clear insight as to how cisplatin may function as an inhibitor to stop the DNA replication process, thus, kill the cell eventually. Their studies show that cisplatin binds to synthetic oligodeoxynucleotides to form cis-[Pt(NH.sub.3).sub.2 {d(pGpG)}], where "d(pGpG)" represents dinucleotide made of deoxyguanosine monophosphate. They indicated that the intrastrand cross-linked cis-[Pt(NH.sub.3).sub.2 {d(pGpG)}] is a very possible reason why cisplatin is capable of inhibiting DNA replication. Fichtinger-Schepman et. al., (Biochemistry, 1985, 24, 707-713) synthesized and identified four adducts of cisplatin and DNA residues. They are: cis-[Pt(NH.sub.3).sub.2 d(pGpG)], cis-[Pt(NH.sub.3).sub.2 d(pApG)], cis-[Pt(NH.sub.3).sub.3 dGMP], and cis-[Pt(NH.sub.3).sub.2 (dGMP).sub.2 ], where "d(pGpG)" represents dinucleotide made of deoxyguanosine monophosphate, "d(pApG)" represents dinucleotide made of deoxyadenosine monophosphate and deoxyguanosine monophosphate, and dGMP represents deoxyguanosine monophosphate.
The most common binding of cisplatin to DNA is through the loss of chloride ion to form Pt-N bond to the N.sub.7 of guanine on deoxyguanosine. Most references indicate that N.sub.7 of guanine is the major binding site for guanosine nucleotide. Examples of the references are F. J. Dijt et al. (J Am. Chem. Soc. 1984, 106, 3644-3647), A. M. J. Fichtinger-Schepman et al. (Biochemistry 1985, 24, 707-713), and S. E. Sherman et al. (Science 1985, 230, 412-417). However, other nucleosides or deoxynucleosides are also known to bind cisplatin (chapter 9, Metal-DNA Chemistry, 1989, American Chemical Society Symposium Series 402, 119-145).
In terms of modifying the composition of the dosage forms of cisplatin, many articles were published. Cisplatin has been used in combination with caffeine by H. Yasutake et al. (Gan to Kagaku Ryoho 1989, 16, 2031-8) and by H. Tsuchiya (Kanazawa Daigaku Juzen Igakkai Zasshi 1988, 97, 543-56). Cisplatin has also been used in combination with cytosine arabinoside and the combination has shown some advantages as shown by J. Berek et al. (Obstet. Gynecol. 1989, 74, 663-6). Another combination, cisplatin and novobiocin, has also been shown to be advantageous by P. Eder et al. (Cancer Research 1989, 49, 595-8. A patent issued in 1992 (U.S. Pat. No. 5,130,145) was related to this invention. This prior art indicates that when cisplatin and L-ascorbic acid are administered simultaneously, the anti-tumor activity is higher.
None of these prior arts uses nucleoside or deoxynucleoside along with cisplatin in a pharmaceutical composition for cancer therapy. The main reason for this is that nucleosides and deoxynucleosides have not been used as pharmaceutical excipients.
This invention comprises a pharmaceutical composition comprising cisplatin, a special carrier, and, optionally, customary pharmaceutical excipients, whereas said special carrier represents one to four nucleosides, one to four deoxynucleosides, or the combination of one to four nucleosides and one to four deoxynucleosides, wherein nucleoside represents adenosine, guanosine, cytidine, or uridine and deoxynucleoside represents deoxyadenosine, deoxyguanosine, deoxycytidine, or thymidine. Said pharmaceutical excipients are customary and physiologically acceptable pharmaceutical excipients such as mannitol, lactose, sodium chloride, phosphates, water, ethanol, hydrochloric acid, magnesium stearate, cellulose, starch, polyethylene glycol, etc. Therefore, the composition may be in a liquid or solid dosage form suitable for parenteral or oral administration to a patient.
This composition is different from the conventional pharmaceutical compositions which do not contain nucleosides or deoxynucleosides.
Based on the studies of R. A. Lerner et al. (Proc. Natl. Acad. Sci. USA, 1971, 68, 1212), J. C. Rogers et al. (J. Immunol. 1981, 126, 703), J. Woo et al. (Biochem. J. 1972, 128, 1273), and D. A. Juckett et al. (Cancer Research 1982, 42, 3565), it was shown that most cancer cells have DNA or RNA sticking out of the cells. Because nucleosides or deoxynucleosides are the building blocks of RNA or DNA, it is conceivable that a drug molecule comprising available nucleoside or deoxynucleoside may be more likely to be grabbed by the DNA or RNA sticking on the outside of the cancer cells, thus, giving the drug molecule better opportunity to attack the cancer cells.
Because the preparation of this composition comprises mixing cisplatin and nucleoside or deoxynucleoside in a suitable solvent for a significant period of time, it contains some of the adducts formed between cisplatin and nucleoside or deoxynucleoside. These adducts may have stronger affinity to the DNA or RNA being replicated. Since most cancer cells are much more active in reproducing DNA or RNA, it can become a more likely target for the adduct formed between cisplatin and nucleoside or deoxynucleoside. As a result, this composition may be less toxic than cisplatin alone or cisplatin in other pharmaceutical compositions. The in-vitro results indicate that it is the case for the cisplatin/guanosine 1:1 adduct as shown in previous patent application (application Ser. No. 08/818,444).
Predominantly, cisplatin binds onto deoxyguanosine of DNA. However, cisplatin also binds onto other deoxynucleosides or nucleosides. Thus, nucleosides or deoxynucleosides, other than guanosine and deoxyguanosine, may also show similar effects in reducing the toxicity of cisplatin even though their affinity to cisplatin may not be as strong as that of guanosine or deoxyguanosine.
Therefore, this invention is a better pharmaceutical composition than other cisplatin compositions.
Because cisplatin binds onto DNA or RNA, this composition may also be used to treat viruses, such as Human Immunodeficiency Virus (HIV), to bind its DNA or RNA and kill the virus. Thus, the composition may be used for the treatment of Acquired Immune Deficiency Syndrome (AIDS) patient. The composition may also be used in combination with other well known AIDS drugs, such as 3'-azidothymidine (AZT), to interfere with the HIV enzyme reverse transcriptase and achieve the goal of hampering the reproduction of HIV.